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The brain of an untreated mouse on the left, showing huntingtin protein aggregation (a hallmark of Huntingtons disease) and on the right, the brain of a mouse treated with CRISPR-Cas9 editing, showing the lack of protein aggregation.

Nicole Déglon

Gene-editing method halts production of brain-destroying proteins

CHICAGO, ILLINOIS—Huntingtons disease, a neurological condition caused by brain-destroying mutant proteins, starts with mood swings and twitching and ends in dementia and death. The condition, which afflicts about 30,000 Americans, has no cure. But now, a new gene-editing method that many believe will lead to a Nobel Prize has been shown to effectively halt production of the defective proteins in mice, leading to hope that a potent therapy for Huntingtons is on the distant horizon.

That new method is CRISPR, which uses RNA-guided enzymes to snip out or add segments of DNA to a cell. In the first time it has been applied to Huntingtons disease, CRISPR’s results are “remarkably encouraging,” says neuroscientist Nicole Déglon of the University of Lausanne in Switzerland, who led the mouse study, results of which she and her co-researcher Nicolas Merienne shared yesterday at the Society for Neuroscience Conference in Chicago, Illinois.

As neurological diseases go, Huntingtons is an ideal candidate for CRISPR therapy, because the disease is determined by a single gene, Déglon notes. A mutation in the gene, which codes for a normally helpful brain protein called huntingtin, consists of different numbers of “tandem repeats,” repeating segments of DNA that cause the protein to fold into a shape that is toxic to the brain. Déglon and her team wondered whether CRISPR could halt production of this dangerous molecule.

Using a virus as a delivery vehicle, the researchers infected two separate groups of healthy adult mice with a mutant huntingtin gene, but only one group received the therapy: a CRISPR “cassette,” which includes DNA for the gene-editing enzyme Cas9 and the RNA to target the huntingtin gene. CRISPR-Cas9 works by “silencing” the part of the huntingtin gene that signals protein production. Researchers hypothesized that by cutting into these so-called “start sites,” they would be able to permanently pause synthesis of the huntingtin protein. If this were true, the mice treated with the CRISPR cassette would have little to no buildup of mutated proteins, and that’s exactly what Déglon and her team saw. After only 3 weeks, the two groups of mice showed a striking contrast: Those without the CRISPR treatment had large areas of protein aggregation, and those with the treatment had almost none—CRISPR’s editing had prevented nearly 90% of the rogue proteins. “Having reached about 90% [blockage of production] changes the story [of Huntingtons therapy] completely,” she says. “It opens new treatment strategies that are based in DNA, and so would have a permanent benefit for the rest of someone’s life.”

Abdellatif Benraiss, a translational neuroscientist at the University of Rochester in New York who is not involved with the research, cautions that the current technique is not poised for that kind of longevity. Because CRISPR cannot yet discriminate between mutant and healthy huntingtin genes (a person typically has one of each and the targeted start site is the same for both copies), it essentially eliminates all huntingtin proteins, even the healthy variety.

“If there is no specificity for mutant huntingtin, that’s a concern—this is not a treatment for 4 weeks or 4 months, this is going to be permanent,” he says. Though the role of healthy huntingtin proteins remains murky, they’re thought to be involved in basic cell functions such transporting materials and chemical signaling. “As bad as too much huntingtin is, we still need one copy [of its gene] so it can do its job in our bodies.”

Déglon is already on the case. Her team plans next to use CRISPR to target individualized differences in the DNA sequences called single nucleotide polymorphisms (SNPs). In many cases, these SNPS are located right next to the mutation on a DNA sequence, effectively flagging it for researchers. Combined with this SNP differentiation, the researchers plan to test the CRISPR-Cas9 treatment in “humanized” mice—mice that, instead of carrying the mouse version of mutant huntingtin, carry two copies of the human gene, one mutant and one healthy. That approach would bring the model closer to how this kind of a CRISPR treatment may act in humans. “We’re just at the beginning of the story,” Déglon says. “There are still many questions to ask, unfortunately.” She pauses and then brightens, “Well, actually, fortunately, too.”